3-(5-phenyl-3h-1,4-benzodiazepin-2-yl) carbazic acid and alkyl esters in therapeutic compositions and method

ABSTRACT

This invention is a therapeutic composition for treating humans and animals comprising a benzodiazepine of the Formula 1 and pharmacologically acceptable acid addition salts thereof in combination with a pharmaceutical carrier and a method for therapeutic treatment.

United States Patent Hester, Jr.

[ 51 Sept. 26, 1972 4] 3-(5-PHENYL-3H-l,4-BENZODIAZEPIN- 2-YL) CARBAZIC ACID AND ALKYL ESTERS IN THERAPEUTIC COMPOSITIONS AND METHOD [72] Inventor: Jackson B. Hester, Jr., Galesburg,

, ch. V a. M r,, [73] Assigneez The Upjohn Company, Kalamazoo, Mich.

[22] Filed: Nov. 18, 1971 [21] Appl. No.: 200,203

Related US Application Data [63] Continuation-impart of Ser. No. 852,112, Aug.

21, 1969, Pat. No. 3,646,055

[52] US. Cl. ..424/244, 260/239 BD [51] Int. Cl. ..A61k 27/00 [58] Field of Search ..SN/852, 112; 424/244;

[56] References Cited OTHER PUBLICATIONS Meguro et' a1., Tetrehedron Letters, No. 47, pp. 4039- 4042 (1970).

Primary Examiner-Stanley J. Friedman Attorney-John J. Killinger et a1.

[ ABSTRACT Therapeutic compositions for treating humans and animals comprising, in unit dosage form, 3-(S-phenyl- 3H-l,4-benzodiazepin-2-yl)carbazic acid and alkyl esters of the formula) 0 NlI--NH-&-0Rr

wherein R R and R are selected from the group consisting ofhydrogen, allgl of 1 to 3 carbon atoms, inclusive, halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoylamino, and dialkylamino, in which the carbon chain moieties are of l to 3 carbon atoms, inclusive,

11 Claims, No Drawings 3-(5-PHENYL-3H- l ,4-BENZODIAZEPIN-2-YL) CARBAZIC ACID AND ALKYL ESTERS IN THERAPEUTIC COMPOSITIONS AND METHOD CROSS REFERENCE .TO RELATED APPLICATION This application is a continuation-in-part of application Ser. No. 852,112, filed Aug. 21, 1969, now US. Pat. No. 3,646,055 issued Feb. 29, 1972.

BRIEF SUMMARY OF THE INVENTION This invention is a therapeutic compositionfortreating humans and animalscomprising a benzodiazepine of the Formula I and pharmacologically acceptable acid addition salts thereof in combination with a pharmaceutical carrier anda method for therapeutic treatment.

DETAILED DESCRIPTION compositions such as tablets, the compound of Formu-- 1a I is mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulos'e, and functionally similar materials as pharmaceutical diluents or carriers. 'Wafers are prepared'in the same manner astablets, differing only in shapeand the inclusion of sucrose or other sweetener and flavor. In their simplest embodiment, capsules, like tablets, are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size. Soft gelatin capsules are prepared by machine encapsulation of a slurry of 'the compound with an acceptable vegetable oil, light liquid petrolatum or other inert oil.

Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared. The

water soluble forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup. An elixir is prepared by using a hydro-alcoholic (ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with a syrup vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used,-can be either suspended or dissolved in the vehicle. Inpreparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into-an suitable vial or ampul and sealing. Advantageously, ad-

juvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The term unit dosage form as used in the specification and claims refers to physically discrete units suitable as unitary dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier, or vehicle. The specifications for the novel unit dosage forms of this invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for use in humans and animals, as disclosed in detail in this specification, these being features of the present invention. Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, pills, suppositories, powder packets, granules, wafers, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampuls, vials, segregated multiples of any of the foregoing, and other forms as herein described.

The dosage of the compound for treatment depends on route of administration; the age, weight, and condition of the patient. A dosage schedule of from about 10 to 200 mg. in a single or divided dose, embraces the effective therapeutic range for which the compositions are effective. The dosage to be administered is calculated on the basis of from about 0. 1 to about 5 mg./kg. by weight of subject.

The compound is compounded with a suitable pharmaceutical carrier in unit dosage form for convenient and effective administration. In the preferred embodiments of this invention, the dosage units contain the compound in: 10, 25, 50, and mg. amounts for systemic treatment; and 0.1 percent to 5.0 percent w/v for parenteral treatment. The dosage of compositions containing a compound of Formula I and one or more other active ingredients is to be determined with reference to the usual dosage of each such ingredient.

In addition to the administration of a compound of Formula I as the principle active ingredient of compositions for treatment of the conditions described herein, the said compound can be combined with other compounds to obtain advantageous combinations of proper-ties. Such combinations include a compound of Formula l with other hypnotics, for example, barbital, 65 to 400 mg.; phenobarbital, 16 to 250 mg.; amobarbital, 65 to 200 mg.; hexobarbita], 250 to 500 mg.; chloral hydrate, 250 to 500 mg.; and methyprylon, 100 to 400 mg.

The following examples are illustrative of the best mode contemplated by the inventor for carrying out this invention and are not to be construed as limiting.

EXAMPLE 1 A lot of 10,000 tablets, each containing mg. of 3- (7-chloro-5-phenyl-3H-l ,4-benzodiazepin-2-yl )carbazic acid ethyl ester is prepared from the following types and amounts of ingredients:

3-(7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl)carbazic acid ethyl ester lOO gm. Dicalcium phosphate L500 gm. Methylcellulose, USP. cps.) 60 gm. Talc I50 gm. Corn starch 200 gm. Calcium stearate l2 gm.

EXAMPLE 2 One thousand two-piece hard gelatin capsules, each containing 10 mg. of 3-(7-chloro-5-phenyl-3H-1,4- benzodiazepin-Z-yl)carbazic acid ethyl ester are prepared from the following types and amounts of ingredients:

3-( 7-chloro-5 -phenyl-3H-l ,4-benzodiazepin-2-yl)carbazic acid ethyl ester 10 gm. Talc 25 gm. Magnesium stearate 250 gm.

The ingredients are mixed well and filled into capsules of the proper size.

Capsules so prepared are useful to produce tranquilization in adults at a dose of one capsule.

EXAMPLE 3 One thousand tablets for sublingual use are prepared from the following ingredients:

3-( 7-chloro-5 -phenyl-3H- l ,4-benzodiazepin-2-yl)carbazic acid ethyl ester 25 gm. Polyethylene glycol 4,000, powdered 150 gm. Polyethylene glycol 6,000, powdered 75 gm.

The ingredients are mixed well and compressed into sublingual-type tablets weighing 250 mg.

These tablets placed under the tongue are useful in producing tranquilization in adults at a dose of 1 tablet.

EXAMPLE 4 encapsulating in the usual manner.

One capsule taken orally by an adult reduces anxiety.

EXAMPLE 5 One thousand tablets, each containing 50 mg. of 3- (7-chloro-5-phenyl-3H-l ,4-benzodiazepin-2-yl )carbazic acid ethyl ester are made from the following types and amounts of ingredients:

3-( 7-chloro-5-phenyl-3H- l ,4-benzodiazepin-2-yl)carbazic acid ethyl ester 50 gm. Lactose 310 gm. Microcrystalline cellulose NF gm. Starch 16 gm. Magnesium stearate powder 4 gm.

, The ingredients are screened and blended together and pressed into 500 mg. tablets.

The tablets are useful to reduce anxiety in adults.

EXAMPLE 6 A sterile preparation suitable for intramuscular injection and containing 10 mg. of 3-(7-chloro-5-phenyl- 3H-l ,4-benzodiazepin-2-yl)carbazic acid ethyl ester in each milliliter is prepared from the following ingredients:

3-( 7-chloro-5-phcnyl-3H- l ,4-benzodiazepin-2-yl)carbazic acid ethyl ester 10 gm. Benzyl benzoate 200 gm. Methylparaben l.5 gm. Propylparaben 0.5 gm. Cottonseed oil q.s. 1,000 ml.

One milliliter of this sterile preparation is injected to reduce anxiety prior to surgical procedures in adults.

EXAMPLE 7 Following the procedure of the preceding Examples 1 through 6, inclusive, dosage forms are similarly performed substituting an equal amount each of 3( 7-chloro-5-(o-chlorophenyl)-3H- l ,4- benzodiazepin-2-yl)-carbazic acid ethyl ester; 3-( 6-chloro-5-phenyl-3l-ll ,4-benzodiazepin-2-yl)carbazic acid ethyl ester; 3-( 7-nitro-5-phenyl-3H-l ,4-benzodiazepin-2-yl )carbazic acid ethyl ester; 3-( 7-fluoro-5-phenyl-3H-l ,4-benzodiazepin-2-yl)carbazic acid ethyl ester; 3-( 7-trifluoromethyl-S-phenyl-3H-l ,4-benzodiazepin- 2-yl)-carbazic acid ethyl ester; 3-( 7-cyano-5-phenyl-3H- 1 ,4-benzodiazepin-2-yl )carbazic acid ethyl ester; 3-( 7-chloro-5-( o-chlorophenyl )-3H- 1 ,4- benzodiazepin-Z-yl)-carbazic acid methyl ester; 3-( 6-ethylthio-5-( o-bromophenyl )-3 H- l ,4- benzodiazepin-Z-yl)carbazic acid methyl ester; 3-( 6,8-dichloro-5-(o-fluorophenyl)-3H-1 ,4- benzodiazepin-2-yl)carbazic acid ethyl ester; 3-( 8-nitro-5-(o-chlorophenyl )-3H- 1 ,4-benzodiazepin- 2-yl)-carbazic acid methyl ester; 3-( 7-bromo-5-(o-bromophenyl )-3H- 1 ,4- benzodiazepin-Z-yl)-carbazic acid ethyl ester; 3-( 7-methylsulfinyl-5-(o-fluorophenyl)-3H- l ,4- benzodiazepin-2-yl)carbazic acid propyl ester; 3-(9-propylsulfonyl-7-methyl-5-phenyl-3H-1,4- benzodiazepin- 2-yl)carbazic acid isopropyl ester; 3-( 7-dimethylamino-5-phenyl-3H- l ,4-benzodiazepin- 2-yl)carbazic acid ethyl ester; 3-(7,8-dicyano-5-(p-methylsulfonylphenyl)-3l-l-1,4- benzodiazepin-2-yl)carbazic acid ethyl ester;

3-( 6-chloro-5-( m-bromophenyl )-3H- 1 ,4- benzodiazepin-Z-yl)-carbazic acid ethyl ester; 3-( 7-methyl-5 -phenyl-3H- l ,4-benzodiazepin-2-yl )carbazic acid ethyl ester; for the 3-(7-chloro-5-phenyl-3H- l ,4-benzodiazepin-2- yl)-carbazic acid ethyl ester of the examples.

I claim:

1. A therapeutic composition comprising in unit dosage form, from about to about 200 mg. of a compound ofthe formula;

wherein R R and R are selected from the group consisting of hydrogen, alkyl of one to three carbon atoms, inclusive, halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoylamino, and dialkylamino, in which the carbon chain moieties are of one to three carbon atoms, inclusive, and wherein R, and R is selected from the group consisting of hydrogen and alkyl of one to three carbon atoms inclusive, including the pharmacologically acceptable acid addition salts thereof in association with a pharmaceutical carrier.

2. The composition of claim 1 wherein the compound is 3-( 7-chloro-5-phenyl-3H- l ,4-benzodiazepin-2 -yl)carbazic acid, ethyl ester.

3. The composition of claim 1 wherein the compound is 3-(7-chloro-5-(o-chlorophenyl)-3H-1,4- benzodiazepin 2-yl)- carbazic acid ethyl ester.

4. A process for reducing anxiety comprising the administration to a human or animal subject of a .tranquilizing amount of a compound of the formula:

I benzodiazepin-Z-yl)-carbazic acid ethyl ester.

wherein R R and R are selected from the group consisting of hydrogen, alkyl of one to three carbon atoms, inclusive, halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio alkylsulfinyl, alkylsulfonyl, alkanoylamino, and dialkylamino, in which the carbon chain moieties are of one to three carbon atoms, inclusive, and wherein R and R is selected from the group consisting of hydrogen and alkyl of one to three carbon atoms inclusive, in association with a pharmaceutical carrier.

5. The process of claim 4 wherein from about 10 to about 200 mg. of the compound is administered.

6. The process of claim 4 wherein the compound is 3- (7-chloro-5-phenyl-3H- l ,4-benzodiazepin-2-yl )carbazic acid, ethyl ester and the amount administered is from about 10 to about 200 mg.

7. A process of claim 4 wherein the compound is 3- (7-chloro-5-( o-chlorophenyl )-3l-ll ,4-benzodiazepin-2 -yl)-carbazic acid ethyl ester and the amount adwherein R R and R are selected from the group consisting of hydrogen, alkyl of one to three carbon atoms, inclusive, halogen, nitro, cyano, trifluoromethyl, and

lk klth, alk l l, alkl lf 1, la y lam i r io an dialky l rl'iii i g m whi cl i tli 23113311 chain moieties are of one to three carbon atoms, inclusive, and wherein R and R is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms inclusive, in association with a pharmaceutical carrier.

9. The process of claim 8 wherein from about 10 to about 200 mg. of the compound is administered.

10. The process of claim 8 wherein the compound is 3-( 7-chloro-5-phenyl-3H- l ,4-benzodiazepin-2-yl )carbazic acid ethyl ester and the amount administered is from about 10 to about 200 mg.

11. The process of claim 8 wherein the compound is 3-( 7-chloro-5-(o-chlorophenyl)-b 3H-l ,4-

33 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No'. 5,694 552 Dated September 26, 1972 Inventor(s) JaCkSon B. Hes t I, J1.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shownrbelowz Column 6, line 55, "-chlorophe nyH b shoeld read -chlorop vU-EH- Signed and sealed this 6th day of March 1973.

(SEAL) Attest:

ROBERT GOTTSCHALK Commissioner of Patents EDWARD M.FLETCHER,JR. Attesting Officer 

2. The composition of claim 1 wherein the compound is 3-(7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl)carbazic acid, ethyl ester.
 3. The composition of claim 1 wherein the compound is 3-(7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl)- carbazic acid ethyl ester.
 4. A process for reducing anxiety comprising the administration to a human or animal subject of a tranquilizing amount of a compound of the formula:
 5. The process of claim 4 wherein from about 10 to about 200 mg. of the compound is administered.
 6. The process of claim 4 wherein the compound is 3-(7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl)carbazic acid, ethyl ester and the amount administered is from about 10 to about 200 mg.
 7. A process of claim 4 wherein the compound is 3-(7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl)-carbazic acid ethyl ester and the amount administered is for about 10 to about 200 mg.
 8. A process for inducing sleep comprising the administration to a human or animal subject of a hypnotic amount of a compound of the formula:
 9. The process of claim 8 wherein from about 10 to about 200 mg. of the compound is administered.
 10. The process of claim 8 wherein the compound is 3-(7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl)carbazic acid ethyl ester and the amount administered is from about 10 to about 200 mg.
 11. The process of claim 8 wherein the compound is 3-(7-chloro-5-(o-chlorophenyl)-b 3H-1,4-benzodiazepin-2-yl)-carbazic acid ethyl ester. 